 |
PDBsum entry 5urm
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Hydrolase/hydrolase inhibitor
|
PDB id
|
|
|
|
5urm
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
References listed in PDB file
|
|
|
Key reference
|
|
|
Title
|
|
Discovery of allosteric inhibitors targeting the spliceosomal RNA helicase brr2.
|
|
|
Authors
|
|
M.Iwatani-Yoshihara,
M.Ito,
M.G.Klein,
T.Yamamoto,
K.Yonemori,
T.Tanaka,
M.Miwa,
D.Morishita,
S.Endo,
R.Tjhen,
L.Qin,
A.Nakanishi,
H.Maezaki,
T.Kawamoto.
|
|
|
Ref.
|
|
J Med Chem, 2017,
60,
5759-5771.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
Abstract
|
|
|
Brr2 is an RNA helicase belonging to the Ski2-like subfamily and an essential
component of spliceosome. Brr2 catalyzes an ATP-dependent unwinding of the U4/U6
RNA duplex, which is a critical step for spliceosomal activation. An HTS
campaign using an RNA-dependent ATPase assay and initial SAR study identified
two different Brr2 inhibitors, 3 and 12. Cocrystal structures revealed 3 binds
to an unexpected allosteric site between the C-terminal and the N-terminal
helicase cassettes, while 12 binds an RNA-binding site inside the N-terminal
cassette. Selectivity profiling indicated the allosteric inhibitor 3 is more
Brr2-selective than the RNA site binder 12. Chemical optimization of 3 using
SBDD culminated in the discovery of the potent and selective Brr2 inhibitor 9
with helicase inhibitory activity. Our findings demonstrate an effective
strategy to explore selective inhibitors for helicases, and 9 could be a
promising starting point for exploring molecular probes to elucidate biological
functions and the therapeutic relevance of Brr2.
|
|
|
|
|
|
|
